Multi-agent System for Obtaining Relevant Genes in Expression Analysis between Young and Older Women with Triple Negative Breast Cancer

Triple negative breast cancer is an aggressive form of breast cancer. Despite treatment with chemotherapy, relapses are frequent and response to these treatments is not the same in younger women as in older women. Therefore, the identification of genes that cause this difference is required. The identification of therapeutic targets is one of the sought after goals to develop new drugs. Within the range of different hybridization techniques, the developed system uses expression array analysis to measure the expression of the signal levels of thousands of genes in a given sample. Probesets of Gene 1.0 ST GeneChip arrays provide categorical genome transcript coverage, providing a measurement of the expression level of the sample. This paper proposes a multi-agent system to manage information of expression arrays, with the goal of providing an intuitive system that is also extensible to analyze and interpret the results. The roles of agent integrate different types of techniques, statistical and data mining methods that select a set of genes, searching techniques that find pathways in which such genes participate, and an information extraction procedure that applies a CBR system to check if these genes are involved in the disease

Obtaining Relevant Genes by Analysis of Expression Arrays with a Multi-Agent System

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite treatment with chemotherapy, relapses are frequent and response to these treatments is not the same in younger women as in older women. Therefore, the identification of genes that provoke this disease is required, as well as the identification of therapeutic targets.There are currently different hybridization techniques, such as expression ar-rays, which measure the signal expression of both the genomic and tran-scriptomic levels of thousands of genes of a given sample. Probesets of Gene 1.0 ST GeneChip arrays provide the ultimate genome transcript coverage, providing a measurement of the expression level of the sample.This paper proposes a multi-agent system to manage information of expres-sion arrays, with the goal of providing an intuitive system that is also extensible to analyze and interpret the results.The roles of agent integrate different types of techniques, from statistical and data mining techniques that select a set of genes, to search techniques that find pathways in which such genes participate, and information extraction techniques that apply a CBR system to check if these genes are involved in the disease

Diagnostic Significance of Exosomal miRNAs in the Plasma of Breast Cancer Patients

Poster Session AbstractsBackground and Aims: Emerging evidence that microRNAs (miRNAs) play an important role in cancer development has opened up new opportunities for cancer diagnosis. Recent studies demonstrated that released exosomes which contain a subset of both cellular mRNA and miRNA could be a useful source of biomarkers for cancer detection. Here, we aim to develop a novel biomarker for breast cancer diagnosis using exosomal miRNAs in plasma. Methods: We have developed a rapid and novel isolation protocol to enrich tumor-associated exosomes from plasma samples by capturing tumor specific surface markers containing exosomes. After enrichment, we performed miRNA profiling on four sample sets; (1) Ep-CAM marker enriched plasma exosomes of breast cancer patients; (2) breast tumors of the same patients; (3) adjacent non-cancerous tissues of the same patients; (4) Ep-CAM marker enriched plasma exosomes of normal control subjects. Profiling is performed using PCR-based array with human microRNA panels that contain more than 700 miRNAs. Results: Our profiling data showed that 15 miRNAs are concordantly up-regulated and 13 miRNAs are concordantly down-regulated in both plasma exosomes and corresponding tumors. These account for 25% (up-regulation) and 15% (down-regulation) of all miRNAs detectable in plasma exosomes. Our findings demonstrate that miRNA profile in EpCAM-enriched plasma exosomes from breast cancer patients exhibit certain similar pattern to that in the corresponding tumors. Based on our profiling results, plasma signatures that differentiated breast cancer from control are generated and some of the well-known breast cancer related miRNAs such as miR-10b, miR-21, miR-155 and miR-145 are included in our panel list. The putative miRNA biomarkers are validated on plasma samples from an independent cohort from more than 100 cancer patients. Further validation of the selected markers is likely to offer an accurate, noninvasive and specific diagnostic assay for breast cancer. Conclusions: These results suggest that exosomal miRNAs in plasma may be a novel biomarker for breast cancer diagnosis.link_to_OA_fulltex

Metastatic Breast Cancer: Biomolecular Characterization and Targeted Therapy

Metastasis is a complex process that remains a major challenge in the clinical management of cancer, because most cancer-related deaths are attributed to disseminated disease rather than the primary tumor. Despite the significant advances in the prediction of prognosis, and therapeutic management of primary breast cancers, coupled with the substantial improvement in our understanding of the molecular determinants of metastasis, breast cancer relapse and death rates remain unacceptably high. The aim of the research presented in this thesis was to characterize the biomolecular heterogeneity of breast cancer across tumor progression stages and to identify novel biomarkers and therapeutic strategies which may improve prognostication and personalization of therapy for women diagnosed with metastatic breast cancer. By analysis of tumor biopsies collected at different stages of disease progression, we showed that, in general, the phenotype of the primary tumor is typically conserved during tumor progression. However, in a clinically relevant number of cases, a phenotypic drift in biomarkers and tumor molecular subtypes occurs longitudinally with disease progression, with a change to a more aggressive phenotype being associated with an inferior clinical outcome. We also uncovered that breast cancer liver metastases are transcriptionally different from metastases in other anatomical sites and identified candidate liver metastasis-selective genes with the potential to specifically predict liver metastatic relapse and more generally, the time to any recurrence in early stage breast cancer. Furthermore, we demonstrated that co-targeting of PARP1 and PI3K may represent an improved and specific treatment strategy for BRCA1 deficient breast cancers. The results we present continue to emphasize the clinical significance of breast cancer heterogeneity and highlight possible ways to improve the accuracy of predicting prognosis and effectively treating patients with metastatic disease, a step towards achieving the promise of personalized cancer management and overcoming the clinical burden of metastatic breast cancer

Chromosomal radiosensitivity and instability in triple negative and/or young breast cancer and Fanconi Anaemia patients in South Africa

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and the Faculty of Medicine and Health Sciences, Ghent University, Belgium in fulfilment of the requirements for the joint degree of Doctor of Philosophy / Doctor in Health Sciences Johannesburg, 2018.Introduction: Breast cancer is the leading cancer in women in South Africa (SA). Triple negative breast cancer (TNBC) is clinically characterised by the lack of expression of estrogen, progesterone and HER2/NEU receptors. These breast cancers occur frequently in young African women and are associated with aggressive disease progression, poor prognosis and BRCA1 mutations. TN patients with operable tumours may undergo surgery under general anaesthetics. Treatment of TNBC poses a clinical challenge as these tumours are unresponsive to hormonal or HER2 targeted therapy. Defects in BRCA1 and other DNA repair genes contribute to chromosomal instability and radiosensitivity and cause irregularities in the cell cycle checkpoints in the S/G2 phase. Studies have shown the overlap of breast cancer susceptibility genes and Fanconi Anaemia (FA) genes. FA is an autosomal recessive disorder defined by cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC) and defects in DNA repair genes. FA patients are known to be radiosensitive and have defects with DNA repair. These patients are at high risk to develop leukaemia and solid tumours that may require radiotherapy. Diagnosis of FA patients often includes detecting chromosomal aberrations induced by a cross-linking agent. Molecular tests are also conducted to identify mutations in FA genes. It has previously been shown that FA patients undergoing radiotherapy display increased clinical radiosensitivity. Evidence suggests that FA patients are chromosomally radiosensitive to ionising radiation (IR). Chromosomal radiosensitivity can be evaluated using the cytokinesis-block micronucleus (CBMN) assay in different phases of the cell cycle. Micronuclei (MNi) serve as biomarkers for radiation-induced DNA damage repair and defects in DNA repair mechanisms can be reflected in chromosomal radiosensitivity. A number of factors could influence the MNi yield such as storage time and temperature, and cytotoxic agents such as anaesthetics. As radiotherapy is considered a principle treatment in the management of TNBC, it is important to investigate in vitro chromosomal radiosensitivity of South African TN breast cancer patients. Chromosomal instability and radiosensitivity of FA patients has previously not been investigated in SA. The overall aim of this study was to investigate chromosomal instability and radiosensitivity of lymphocytes in South African breast cancer patients, FA patients and parents compared to healthy individuals using the G0 and S/G2 CBMN assay. The effect of age, ethnicity and mutations in breast cancer susceptibility genes was also investigated. Furthermore, storage time and effect of anaesthetics on MNi yield was investigated. Methods: For the G0 MN assay, heparinised blood in culture medium was irradiated at 0Gy (Baseline), 2 and 4 Gy followed by the immediate stimulation of lymphocytes using phytohaemagglutinin (PHA). Cytochalasin B was added 23 hours later to inhibit cell division. The S/G2 MN assay is a modified version of the G0 MN assay. In this assay, the cultures are first stimulated with PHA and irradiated 72 hours post stimulation. Eight hours post irradiation cells were fixed. The Mitomycin C (MMC) MN assay is similar to the G0 MN assay except the DNA damage is induced using MMC. Results: Chromosomal instability is significantly elevated in TNBC, young and older breast cancer patients. Radiation-induced MN values in the G0 MN assay are significantly enhanced in a total unselected group of breast cancer patients compared to healthy individuals. However, when subdividing the breast cancer patients in a TNBC group, the enhanced radiation-induced MNi are not observed. We cannot demonstrate a correlation between the age of the patients and chromosomal radiosensitivity but an effect of ethnicity is noted in our breast cancer population. In the S/G2 MN assay, TNBC patients continued to exhibit a decreased chromosomal radiosensitivity. We also demonstrated that increased storage time can influence MNi yields in patients and controls; anaesthetics influenced spontaneous MNi yields. The FA patients in our study demonstrate higher MNi when compared to parents and controls indicating chromosomal instability and chromosomal radiosensitivity in the G0 as well as in the S/G2 phase of the cell cycle. This is not seen in the FA heterozygotes. With the MMC assay, the detection of significantly higher MN is noted in as well the FA patients as well as the FA carriers. Conclusions: Chromosomal instability and radiosensitivity of breast cancer and FA patients are notably higher when compared to healthy individuals. The association of BRCA mutations in TN and young patients highlight the importance of radiosensitivity information in the understudied SA population. FA carriers can be at risk for breast cancer with mutations associated with breast cancer susceptibility genes. As a functional assay, the MMC MN assay will be useful in the identification of FA carriers who may be at risk of breast cancer. Data on radiosensitivity of patients with defects in DNA repair genes could provide important information for radiotherapy management of cancer.LG201

Spring 2019 Undergraduate Research and Creative Inquiry Symposium Book of Abstracts

BOOK OF ABSTRACTS SPRING 2019 NC A&T STATE UNIVERSITY UNDERGRADUATE RESEARCH & CREATIVITY SYMPOSIU

Treatment Strategies and Survival Outcomes in Breast Cancer

Treatment strategies for breast cancer are wide-ranging and often based on a multi-modality approach, depending on the stage and biology of the tumour and the acceptance and tolerance of the patient. They may include surgery, radiotherapy, and systemic therapy (endocrine therapy, chemotherapy, and targeted therapy). Advances in technologies such as oncoplastic surgery, radiation planning and delivery, and genomics, and the development of novel systemic therapy agents alongside their evaluation in ongoing clinical trials continue to strive for improvements in outcomes. In this Special Issue entitled, ‘Treatment strategies and survival outcomes in breast cancer’, a number of original research articles are included covering a diversity of studies, from pre-clinical and translational biomarker studies to clinical trials and population-based studies. They evaluated survival and other outcomes, including quality of life, in the context of pre-diagnosis (screening), as well as early and advanced stages of breast cancer

An Exploration of the Lives of Young, African American Women with Triple-Negative Breast Cancer

Compared to other subtypes of breast cancer, triple-negative breast cancer: TNBC) accounts for a disproportionate number of metastatic cases and cancer deaths. Glaring disparities are present in the occurrence of TNBC, such that those diagnosed are more likely to be African American: prevalence of 26% vs. 16% in non-African Americans) and premenopausal: 24% vs. 15% postmenopausal). A critical factor to consider regarding the disparities associated with TNBC is the evidence documenting the link between psychosocial stress over the life course and the occurrence of large, aggressive tumors that are characteristic of this subtype. Because issues such as crime, isolation, stress, discrimination, and other factors associated with poverty have been found to significantly affect etiology of breast cancer among young, African American women, it is critical to also consider these issues after diagnosis occurs. Despite the fact that many of these factors impact the etiology of TNBC, little is known about how these factors come into play once the diagnosis has occurred. The present study qualitatively explores the critical biopsychosocial history and current environment of women facing such a diagnosis in order to shed light on the experience of TNBC. Using a grounded theory approach, in-depth, qualitative interviews were conducted with six women with TNBC and with a comparison group of six women with ER+ breast cancer. A prospective, longitudinal design was used with all women in the study to assess change over time and to cultivate prolonged engagement with participants. Data collection occurred in three waves, which corresponded with three critical points of the cancer care trajectory. Findings from this study demonstrate that the following stressors and strengths were unique for women with TNBC as compared to women with ER+ breast cancer: burden carriers throughout the life course, distant/strained relationships with mothers, absent fathers, experiences of sudden, unexpected deaths of loved ones, limited engagement in a spiritual community, limited engagement in neighborhood/community, and young age at time of diagnosis. Findings from these interviews resulted in a preliminary conceptual framework for understanding the contextual lives of women with TNBC, which can assist with guiding the formation of appropriate social work interventions

Use of neoadjuvant chemotherapy in locally advanced breast cancer in the Netherlands

Use of neoadjuvant chemotherapy in locally advanced breast cancer in the Netherlands P.E.R. Spronk1, A.C.M. Van Bommel1, S. Siesling2,3, M.J.T. Baas- Vrancken Peeters4, C.H. Smorenburg5. 1Leiden University Medical Centre, Surgery, Leiden, Netherlands; 2Comprehensive Cancer Centre the Netherlands IKNL, Epidemiology, Utrecht, Netherlands; 3University of Twente, MIRA Biomedical science and Technical Medicine, Twente, Netherlands; 4Netherlands Cancer Institute/Antoni van Leeuwenhoek, Surgery, Amsterdam, Netherlands; 5Netherlands Cancer Institute/Antoni van Leeuwenhoek, Medical Oncology, Amsterdam, Netherlands Background: Neoadjuvant chemotherapy (NAC) is the treatment of choice for patients with locally advanced breast cancer (LABC). The aim of this study is to examine the use of NAC for LABC in all Dutch hospitals participating in breast cancer care and to assess what patient, tumour and hospital characteristics influence its use. Material and Methods: Data were derived from the national multidisciplinary NABON Breast Cancer Audit (NBCA), regarding all women aged >18 years and newly diagnosed with LABC from January 2011 to September 2013. Multivariable logistic regression was used to assess the association between the use of NAC and patient, tumour and hospital related factors. Results: Of 1419 woman diagnosed with LABC, 70% were treated with NAC. This percentage varied from 12.5% to 90% between hospitals and did not increase over time. Factors associated with the use of NAC included young age, large tumour size, more advanced nodal disease and triple negative or hormone-receptor negative tumours. Also patients treated in hospitals with a multidisciplinary preoperative work-up and participation in neoadjuvant studies were more likely to receive NAC. However, considerable variation between hospitals remained after casemix correction. Table 1. Multivariable odds ratios (ORs) for receipt of NAC among 1419 stage III patients 2011 through 2013 OR 95% CI P-value Age 0.000 5 cm 5.68 2.34−13.79 Clinical nodal status 0.000 cNx/N0 ref. cN1 1.32 0.86−2.04 cN2 2.93 1.18−7.29 cN3 10.28 4.18−25.25 Receptor status 0.000 Triple negative 2.35 1.40−3.93 HR−, Her2+ 3.37 1.67−6.78 HR+, Her2+ 0.91 0.51−1.60 HR+, Her2− ref. Type of surgery 0.026 Breast conservation therapy 2.05 1.09−3.84 Mastectomy ref. Multidisciplinary team 0.021 Yes 1.98 1.11−3.53 No ref. Type of hospital 0.569 General 1.20 0.73−1.98 Top clinical ref. Academic 1.50 0.64−3.47 Hospital surgical volume 0.729 200 1.27 0.70−2.31 Study participation 0.005 Yes 1.80 1.20−2.70 No ref. Conclusions: There is considerable variation in the use of NAC for LABC in the Netherlands. Although various patient, tumor and institutional factors are associated with the use of NAC in LABC, these can only explain part of the observed variation in treatment patterns between hospitals